Stroke is a common cause of death and disability throughout the world. Intravenous tissue plasminogen activator (t-PA) is the only FDA-approved therapy for treatment of patients with acute ischemic stroke. However, t-PA use is limited by its narrow therapeutic window, the risk of intracerebral hemorrhage and neurotoxicity. Thus, there is an urgent need for safe and effective new therapies for stroke administered either singly or in combination with intravenous tPA. Activated protein C (APC), a serine protease with direct neuronal and vascular anti-apoptotic activities, and with systemic anticoagulant and anti-inflammatory activities, has been shown to reduce infarct volume, improve behavior and motor neurological function, control neurotoxic effects of t-PA, and increase cerebral blood flow in different animal models of ischemic stroke, in 2 independent laboratories, and in 2 different species. Based on over 30 studies in large and small animals, APC has not been associated with hemorrhage, and appears to meet most of the STAIR criteria established for evaluating potential preclinical neuroprotective agents. APC is FDA-approved for treatment of severe sepsis in humans and was not associated with an increased risk of intracerebral hemorrhage in two large clinical trials of patients with sepsis. Major bleeding events that did occur were often associated with invasive procedures, thrombocytopenia and meningitis, conditions that would be exclusionary for this trial. The proposed pilot, multi-center dose-escalation trial will test the hypothesis that intravenous APC can be administered safely to eligible patients within 0-6 hours of symptom onset of acute ischemic stroke. Seventy-two patients will be enrolled across 5 centers nationwide to receive either intravenous APC in a dose-escalation design using the following dosage tiers: 10, 15, 22, 33, 50, and 75 micrograms/kg. Patients will receive 50% of the total dosage as a bolus injection and the remaining 50% as a continuous infusion over 1 hour. We will determine the safety and feasibility of intravenous APC in patients with acute ischemic stroke (aim 1), the pharmacokinetics of intravenously administered APC in stroke patients (aim 2) and will collect preliminary data on APC's neuroprotective effects using standardized tools of assessment (aim 3). This should enable us, based on the outcome of the proposed pilot study, to design and conduct a larger Phase II safety and efficacy trial of APC in patients with acute ischemic stroke. [unreadable] [unreadable] [unreadable]